Publication Date:
2019
Description:
〈p〉The stringent response enables 〈i〉Mycobacterium tuberculosis〈/i〉 (〈i〉Mtb〈/i〉) to shut down its replication and metabolism under various stresses. Here we show that 〈i〉Mtb〈/i〉 lacking the stringent response enzyme Rel〈sub〉Mtb〈/sub〉 was unable to slow its replication rate during nutrient starvation. Metabolomics analysis revealed that the nutrient-starved 〈i〉rel〈sub〉Mtb〈/sub〉〈/i〉-deficient strain had increased metabolism similar to that of exponentially growing wild-type bacteria in nutrient-rich broth, consistent with an inability to enter quiescence. Deficiency of 〈i〉rel〈sub〉Mtb〈/sub〉〈/i〉 increased the susceptibility of mutant bacteria to killing by isoniazid during nutrient starvation and in the lungs of chronically infected mice. We screened a pharmaceutical library of over 2 million compounds for inhibitors of Rel〈sub〉Mtb〈/sub〉 and showed that the lead compound X9 was able to directly kill nutrient-starved 〈i〉M. tuberculosis〈/i〉 and enhanced the killing activity of isoniazid. Inhibition of Rel〈sub〉Mtb〈/sub〉 is a promising approach to target 〈i〉M. tuberculosis〈/i〉 persisters, with the potential to shorten the duration of TB treatment.〈/p〉
Electronic ISSN:
2375-2548
Topics:
Natural Sciences in General